Nu-monosubstituted-2, 2-dialkyl-1, 3-propanediol dicarbamates



2,237,110 Patented May 17, 1960 spasm is meprobamate (2-methyl-2-n-propyl-1,3-propane- 7 119 diol dicarbamate). The muscle relaxant action of mepro- N-MONOSUBSTITUTED-2,2-DIALKYL-1,3-

' PROPANEDIOL DICARBAMATES bamate is similar to that of mephenesin but of greater potency and longer duration.

.5 This invention is based on the discovery that certain Frank M. Berger, Princeton, and Bernard J. Ludwig, novel compounds, and more particularly certain N-mono- North Brunswick, NJ., assignors to Carter Products, substituted-2,2-dialkyl-1,3--propanediol dicarbamates, posl u New York, a corporation of Maryland sess strong muscle relaxant activity. The invention also O A 6 J 11 1959 includes novel methods for producing N-substituted di- No Drawmg pp lea on 1o carbamates exemphfied by the novel compounds of this Serial No. 819,552

7 Claims. (Cl. 167-65) This invention relates to novel organic compounds invention. term propyl means normal (11) propyl.

The novel compounds of this invention are disclosed in the following Table I, which is as follows:

In the present specification and claims, the

TABLE I N-monosubstztuted-2,2-d1alkyl-1 ,3-propanediol dzcarbamates 9 H R\ /CH /C\ X R OH O (ENE.

Analysis M.P., 0, or

Dist. temp., 0, X R R Formula 7 u and pressure, PD LD N. N' mm.

Cale. Found 11. 38 11.37 M.P., 71.5-73.5 165 580 11. 38 11. 08 P 88 130 730 10. 76 10. 136 570 1 11.45 11. 74 180 510 y} 11.38 11.06 1. 4677 154-156 (0.05)---- 170 700 CmHztOtN}- 10. 76 10.71 1.4694 144-147 (0.02) 146 790 isopropyl- C12H2t04N2- 10.76 10.76 M.P., 89-91- 153 790 n-butyl' C1sH25Q4Nz- 10. 21 10. 42 M.P., 49- 94 514 isobutyl--- d CmHmOrN 10. 21 10. 47 1. 4645 -110 (0.01).--- 175 940 yl d OmHrzOrNz- 10.85 11. 03 l. 4760 -130 (0.25) 114 500 propargyL... do do C 2H2u04Ng 10. 93 11. 34 M.P., -96 172 650 isopropy do isopropyL- G H24O4N 10. 76 10. 98 760 n-butyl-. d0 C 3HzsO4Nz 10- 21 9. 96 560 allyl do do 1zH2z 4 10.85 11.20 197 530 methy n-butyl- C1iH22O-i 11.38 ,ll. 30 160 515 propy1 do 10.21 10.49 114 532 lsopropyl 10. 21 10. 23 102 840 lyl- 10. 28 10. 20 136 345 propargy 10. 36 10. 29 136 345 propyL. 10. 21 10. 20 195 620 isopropyL 10.21 10. 47 .P., 78-80"--- 90 555 allyl 10.28 10. 15 1. 4830 120-125 (0.002).-- 102 344 propargyl. O13HzzO4N-z 10. 36 10. 10 1.4862 120-125 (0001)... 171 510 propy1 C HuOrNz- 10.76 10.96 M.P. 147 760 ISOPI'OP CmHnOqNz. 10. 7G 10. 83 130 1, 280 yl CQHMOINI- 10. 83 10. 64 205 330 lsopropyL propyl. (l HreOiNr 10. 21 10. 51 225 880 isopropyl. isopropyL. C13H26o4 2 10. 21 10. 23 120 730 methyl (1 n-butyL C1zH2404 2 6 73 509 propargyl d0 d0 O 4Hz4O4Nz 9. 85 9- 71 153 510 The novel compounds of this invention possess unand has for its object the provision of new compounds expected muscle relaxant activity. In order to show the possessing muscle relaxant action of high activity.

Prior to this invention, many drugs have been used for the purpose of relieving muscle spasm caused by different disorders, such for example, as rheumatic and related disorders, cerebral palsy, and various neurological conditions. For many years, salicylates were used for this purpose but they were not generally efiective for they relieved aching discomfort for only a short time. Later, mephenesin (3-o-toloxy-1,2-propanediol) became widely used in a variety of conditions where muscle spasm is a factor. The very short duration of action of mephenesin is its greatest drawback. The most recent drug'which has had wide acceptance for relieving muscle a 3 III, there are given corresponding PD and LD values for a number of N, N or N, N disubstituted, N, N, N trisubstituted and N, N, N N tetrasubstituted 2-alkyl or 2,2-dialkyl-l,3-propanediol dicarbamates which possess inferior muscle relaxant activity when compared to the not more than one, of the four hydrogen atoms attached to the carbamate nitrogens. As evidenced by the results in Table I and Table III, it has been found that in general substituting aliphatic groups for more than one of the four hydrogens attached to the two carbamates of compounds of this invention. 5 meprobamate decreases rather than enhances muscle TABLE 11 relaxant activity.

Moreover, from a comparison of the results in Table 1 I and in Table II, it is seen that not every N-substituted 2,2-dialkyl-1,3-propanediol dicarbamate has improved 0 x activity. over meprobamate. The nature of the aliphatic \CH,o group substituted on the N-atom afiects the activity. Also H the nature of the 2,2-dialkyl groups afiects the activity. 0 The unexpected improved muscle relaxant activity of 15 the compounds of this invention is clearly shown by the X R fact that other members of the very specific class to which thecompounds of this invention belong, i.e., N-monosub- Egg??? E 5:38 stituted-2,2-dialkyl-1,3-propanediol dicarbamates, posmethyl methyl 020 sess muscle relaxant activity far inferior to that possessed $33 2},- 3g :38 by meprobamate, and, of course, even'more inferior to 1,002 the unique muscle relaxant activity of the compounds 128 of this invention. 940 The compounds covered by this application are color- 523? less liquids of high boiling point or low melting solids. They are soluble in most organic solvents but only slight- 900 1y soluble in water at ordinary room temperature. They 33 are readily hydrolyzed by hot caustic or strong acld solution to give the corresponding diol, ammonia, prigg mary amine and carbon dioxide. 580 3 The compounds of this invention may be prepared 5328 by many different methods. One method involves reacting an appropriate N-substituted hydroxalkyl carbam- 420 238 ate with a compound selected from the group consistphenyl 280 280 mg of a carbamate of a low boiling alcohol (e.g., an 35 alcohol having 1 to 4 carbon atoms) and cyanic acid.

TABLE III I 01110 C|J-N\ X X R cmo G-N ll X R R1 X Y X1 Y1 PDau H methyl methyL- 520 620 mam-11--.- do do 520 620 propyl .do -.do 570 900 o hyl hyl 370 735 isopropyl hyl 420 420 pheny1 d 420 420 315 730 500 1,020 isopropyL. 620 620 n-butyl 620. 620 isopropy1 methyl 620 620 ethyl ethyl 457 800 methyl-- 420 420 d et 420 420 420 420 conv 940. conv- 650 In evaluating the results reported in Table I, meprobamate (Z-methyl-Z-n-propyl-1,3-propanediol dicarbamate), a known muscle relaxant, is used for comparison purposes, meprobamate having a PD value of 235 mgs/kg. and an LD value of 800 mgs./kg. It is seen that all of the compounds of Table I possess enhanced muscle relaxant activity when compared to meprobamate, while all of the compounds of Table Hand Table III are inferior to meprobamate as a muscle relaxant. From a study of the results reported in Tables I-III, it appears that the enhanced activity of the compounds of this invention, which are disclosed in Table I, appear to be dependent upon the substitution of an aliphatic group for one, and

Cyanic acid is a compound formed by the treatment of an alkali cyanate with anhydrous hydrogen chloride. The N-substituted hydroxyalkyl carbamate employed in the above reactions may be prepared by any of the known methods, some of which are described hereinlater. Another method for producing the compounds of this invention involves the conversion of an appropriate N-unsubstituted hydroxyalkyl carbamate to the desired compound by reacting it with the appropriate organic isocyanate. The N-unsubstituted hydroxyalkyl carbamarte used in this reaction may be prepared by any of the known methods, some of which are described hereinafter. Another method for preparing the compounds of this in;-

vention involves the phosgenation of the appropriate N-unsubstituted hydroxyalkyl carbamate followed by amidation using the desired primary amine.

In order to describe more particularly a number of methods which may be employed forproducing both the intermediate N-substituted' monocarbamates (i.e., hydroxyallryl carbamates) and N-unsubstituted monocarbamates, as well as the compounds of this invention produced therefrom, the following explanation is given. In all instances, the compounds of this invention are prepared from the appropriate 2,2-dialkyl-1,3-propanediol by stepwise carbamation. One method of preparation of the compounds of this inventioninvolves (a) conversion of the diol to the corresponding cyclic carbonate ester (m-dioxanone) using diethyl carbonate, (b) treatment of the cyclic carbonate ester with the appropriate amine NH X, either in aqueous solution or in the anhydrous form, to give the N-substituted monocarbamate, and (0) reaction of the latter compound with a carbamate of a low boiling alcohol such, for example, as urethane, in an ester exchange reaction to give the desired compound. These reactions are summarized in the following reaction scheme wherein R and R are appropriate alkyl radicals.

Alternatively the dicarbamate product of step (c) may be prepared by reacting the monocarbamate of step (b) with cyanic acid (HOCN). r

The monocarbamate obtained from step (b) above may also be prepared by the controlled action of phosgene on the diol (d) followed by amidation with ammonia or the desired amine, NH X(e):

R CHgOH CHzOH When the product of step (e) or the product of step (b) obtained by using ammonia is the N-unsubstituted amide it may be converted to the desired product by phosgenation (f) followed by amidation using the desired primary amine NH X(g) R CHQOH R GH'zO -(J-Cl c001, NHzX H (I) ll R1 orno-o-avn, R1 omo-o-Nm n omon b 1 Ii (h) n n omd-c-mar R1 onto-c4111,

Q When the product of step (e) is the N-aliphatic amide, it may be converted to the final product by either the phosgenation-amidation steps and (g) using ammonia as the amidation agent, or by an ester exchange reaction using a carbamate of a low boiling alcohol such, as for example, urethane, or by reacting the monocarbamate with cyanic acid (i).

cyanic acid O CHzOH R CHSO OCOHB I 1 R R CH:O ONE:

R CHgO ONHI In order to illustrate the preparation of the compounds of this invention the following examples are given illustrating various methods of preparation. Unless otherwise indicated, the parts given are by weight. Examples A-J illustrate the preparation of intermediate compounds used for forming the novel compounds of this invention. Examples 1 to 17 illustrate the preparation of novel compounds of this invention.

Example A illustrates the preparation of the new 2,2- disubstituted-l,3-propanediols used as a starting material in obtaining some of the desired compounds. Example B illustrates the preparation of the intermediate 5,5-disubstituted-Z-m-dioxanones by step (a) described above wherein the diol is converted to the cyclic carbonate ester using diethyl carbonate. Examples C-G illustrate the preparation of a number of intermediates of the compounds of this invention employing step (b) described above by treatment of the cyclic carbonate ester with an appropriate amine or ammonia to give the monocarbamate. Example H illustrates a method for preparing the intermediate chlorocarbonate by step (d) described above by controlled action of phosgene on the diol, while Examples I and J illustrate the preparation of the intermediate monocarbamate by amidation of the chlorocarbonate with the desired amine.

Example 1-7 illustrate the preparation of the compounds of this invention employing steps (c) and (i) described hereinbefore, i.e., reaction of N-substituted monocarbamate with a carbamate of a low boiling alcohol in an ester exchange reaction. Examples 8-11 illustrate different methods for the preparation of some of the compounds of this invention utilizing steps (f) and (g) described above. In Examples 8, 9 and 10 an N-unsubstituted monocarbamate is converted to the desired compound by phosgenation followed by amidation with the appropriate primary aminefi In Example 11, the compound of Example 8 is obtained by phosgenation of the N-substituted monocarbamate and reaction of the monochlorocarbonate with ammonia. Example 12 illustrates a method for the preparation of one of the compounds of this invention employing step- (h). In

appropriate organic 'isocyanate.

EXAMPLE A Preparation of Z-methyl-Z-sea-butyl-I,3-propanedil 92 gms. of diethyl-sec.-butyl methyl malonate were reduced in the usual manner using 22.8.gms. of lithium aluminum hydride in a suitable volume of anhydrous ethyl ether. The mixture was treated with 10% sulfuric acid and the ether soluble components extracted. The ether solution was dried, using a suitable drying, agent, and the residue obtained by the removal of the ether was purified by distilling under reduced pressure. This material was further purified by redistillation. Approximately 46 gms. of 2-methyl-2-sec.-butyl-1,3-propanediol were obtained as a clear colorless liquid, boiling point 92-97 C. (0.1 mm. pressure). Refractive index, N =1.4587. Solubility in water approximately 0.5%. Analysis, calculated for C H O C, 65.7%; H, 12.4%. Found: C, 66.1%; H, 12.1%.

2-ethyl-2-propyl-1,3-propanediol was prepared as de scribed above from diethyl ethyl propyl malonate. The purified product melted at 37-39 C.

EXAMPLE B Preparation of 5-methylJ-propyl-Z-m-dioxanone 132 parts of 2-methyl-2-propyl-1,3-propanediol and 113 parts of diethyl carbonate were mixed in a suitable vessel equipped with an eificient distillation column. The mixture was freed from moisture by distillation of a small portion of the diethyl carbonate. After cooling, approximately one part of sodium ethylate was added. Distillation was continued until substantially the theoretical quantity of ethanol was distilled at about 78 C. A further quantity of parts of diethyl carbonate was added and distillation continued until ethanol removal was complete. The mixture was cooled and diluted with an equal volume of diethyl ether. This solution was washed with dilute hydrochloric acid saturated with sodium chloride and then with water. It was dried using a suitable drying agent and the solvent removed. The residue was distilled under reduced pressure. The fraction distilling at 125-130 at about 0.1 mm. was collected as a clear, colorless, oily liquid. Refractive in dex, N =l.4506. A yield of 80% of the theoretical amount of S-methyl-S-propyl-2-m-dioxanone was obtained.

Other 5,5-disubstituted-Z-m-dioxanones prepared by this method are as follows:

, 5 parts of 5-methyl-S-propyl-Z-m-dioxanone and 7.5 parts of liquid ammonia were placed in a cooled stainless steel pressurebomb and the vessel sealed. The vesselwas permitted to warm to room temperature and al.- lowed to remain at this temperature with occasional shaking for 24 to 48- hours.' The vessel was cooled, opened, and the excess ammonia allowed to evaporate. The monocarbamate which was obtained as a low melting solid was purified by crystallization from a tolueneligroin mixture. Approximately four parts of the puritied product were obtained in the form of a colorless crystalline solid, slightly soluble in water, melting point 61.562.5 C. Y

Other N-unsubstituted monocarbamates prepared by the method of this example are as follows:

Melting Compound Point,

degrees 2-methyl-2-ethyl-3-hydroxypropyl carbamate 43-45 2methyl-?aisopropyl-3-hydroxypropyl carbamate 73-74 2 methyl-2-n-butyl-a-hydroxypropyl carbamate. 65-66 2-ethyl-2-lsopropyl-3-hydroxypropyl carbamate 58-60 EXAMPLE D 7 Preparation of -N-propyl-Z-methyl-2-pr0pyl-3-hydroxy:

' propyl carbamate EXAMPLE B Preparation of N-ethyl-Z-methyl-2-propyl-3-hydroxypropyl carbamate 158 partsof 5-methyl-5-propyl-2-m-dioxanone were stirred at room temperature with 75 parts of a 70% solution of ethylamine in water, until reaction was complete. The excess amine was removed by dissolving the mixture in ether and extracting with dilute hydrochloric acid. The ether was removed from the organic layer and the residue purified by distillation at reduced pressure. The fraction distilling at -112 at 0.02 mm. was collected. Refractive index, N =1.4589.

EXAMPLE F Preparation of N-isobutyl-Z-metlzyl-Z-pr0pyl-3-hydr0xypropyl carbamate 55 parts of 5-methyl-5-propyl-2-m-dioxanone, 51 parts of isobutylamine ad 75 parts ethanol are permitted to remain at room temperature overnight. The ethanol and excess amine are then removed by distillation under reduced pressure. The oily residue remaining is dissolved in ethylether and extracted with dilute hydrochloric acid to remove the remaining amine and then extracted with water. The ether solution is dried over a suitable drying agent and freed from solvent by evaporation. The crude N isobutyl 2 methyl 2 propyl 3- hydroxypropyl carbamate is purified by distillation under reduced pressure; the fraction boiling at 118-119 C. at 0.06 mm. pressure is collected. A yield of 50 parts (62% of theoretical) of purified compound is obtained. Refractive index, N =1.4586.

EXAMPLE G Preparation of N-allyl-Z-methyl-Z-propyl-3-hydroxypr0pyl carbamate then removed by distillation under reduced pressure and the residue purified by vacuum distillation. A yield of 40 parts of purified product distilling at 102-104 C. at 0.05 mm. pressure is obtained. Refractive index, N =1.4683.

Additional N-substituted monocarbamates prepared by the method given in Examples D-G- above are as follows:

Distillation Compound N, Temp, C.

p (Pressure mm.)

N isopropyl 2 methyl -2- propyl 3 -hydroxy- V propylcarbamate 1.4543 8688 (0.01) N-n-butyl-2-methyl-2-propylr3-hydroxypropyl cnrbamate 1.4579 107-108 (0.01) N-propargy1-2-methyl-2-propy1-3-hydroxypropyl carbamate 1. 4663 120-125 (0.06) N-methyl-2-methyl-2-n-butyl-3-hydroxypropyl carbamate 1.4592 96-99 (0.04) N-isopropyl-2-methyl-2-sec.-butyl-3-hydroxypropyl carbamate 1.4631 126-128 (0.07) N-propargyl-2-methyl-2-sec -but l-3-hydroxypropyl carbamete. 1.4790 123-126 (0.04) N-methyl-2-ethyl-2-n carbamate 1.4646 128-130 (0. 06) N -propyl-2 -methy1-2 sec. butyl -3-hydroxypropyl carbamate 1.4655 127-132 (0. 07) N-allyl-2-methyl-2-sec.-butyl-3-hydroxypropyl Ncarbamlatzen.5; 1 nfiflfflfifi. "i, 1.4742 147-148 (0.07)

-p py y -e y y rp p N(3iBI'b&m5t18 2.-.%i1 l 2 l 3 1 l &r -1. 1.4639 130-131 (0.02)

- sopropy e y -propy y oxypro y carbamate 1. 4619 130-132 (0.5)

EXAMPLE H Preparation of 2-methyl-2-propyl-3-hydroxypropyl chlorocarbonate A cooled 10% solution of 1 mole of phosgene in toluene was added with stirring to a cooled solution of 1 mole of 2-methyl-2-propyl-1,3-propanediol and 2 moles of dimethylaniline also dissolved in toluene, at such a rate that the temperature of the mixturewas maintained at about 25 C. The mixture was allowed to remain at this temperature for several hours, then cooled and extracted with cold 5% hydrochloric acid solution to ref move the dimethylaniline. The toluene layer was dried using a suitable drying agent and the chlorocarbonate used in subsequent reactions in the form of its solution in anhydrous toluene.

EXAMPLE I v. Preparation of N-n-butyl-Z-methyl-2-propyl- 3-hydr0xypr0pyl carbamate EXAMPLE. 'I

Preparation of N-iso'propyl-Z-methyZ-Z-propyl- 3-hydroxypropyl carbamate This compound was prepared from 2-methyl-2-propyl- 3-hydroxypropyl chlorocarbonate and isopropyl amine by the method used in Example I. This compound is a liquid having a boiling point of 8688 C. (0.01 mm. pressure). Refraction index, N =l.4543.

PREPARATION OF COMPOUNDS OF THIS INVENTION EXAMPLE 1 Preparation of N-propyl-Z-methyl-2-pr0pyl- 1,3-propanediol dicarbamate 22 parts of N-propyl-Z-methyl-2-propyl-3-hydroxypropyl carbamate and 10 parts of ethyl urethane were dissolved in 250 parts of anhydrous xylene in a suitable vessel equipped with an. eflicient' distillation column. Two parts of aluminum isopropylate were added and the mixture heated to boiling and distillation continued until substantially the theoretical quantity of ethanol had been distilled in the form of an azeotrope. with xylene. The bulk of the solvent was removed by distillation under reduced pressure. parts of water were added and distilled under reduced pressure to remove the final traces of xylene. 50 parts of isopropanol were. added and distilled to remove residual water, and the residue taken up in 100 parts isopropanol. The solution was clarified by filtration, concentrated by evaporation of the isopropanol and the residue subjected to distillation under reduced pressure. The fraction distilling at.l44-l47 at 0.02 mm., was-collected. This product. was obtained in a yield of 72% of theoretical in the form of a somewhat viscous, clear, oily liquid. having the properties listed in Table I. a 1

EXAMPLE 2 Preparation of N-isopropyl-2-methyl-2-propyl- 1,3-propanediol' dicarbamate 7 I EXAMPLE 3 Preparation of N-n-butyI-Z-m-ethyZ-Z-propyl- 1-,3'-propanediol dicarbamate This compound was prepared from N-n-butyl-Z-methyl- 2-propyl-3-hydroxypropyl carbamate and ethyl urethane by the method described in Example 1. The properties and analysis of the purified product are listed in Table 1.

EXAMPLE 4 Preparation. of N-ethyl-Z-methyl-2-propyl!1,3- tpropanediol dicarbamate 22 parts of N-ethyl-2-methyl-2-propyl-3-hydroxypropyl 'carbamate were reacted in an ester exchange reaction with 15 parts ofethyl urethane using aluminum isopropylate as catalyst in anhydrous xylene as described in Example 1'. The product obtained had the properties and analysis as listed in Table I.

EXAMPLE 5 Preparation of N-isobutyl-Z-methyl-Z-propyl-I,3-

propanediol dicarbamale 22.1 parts of N-isobutyl-2-methyl-2-propyl-3-hydroxypropyl carbainate and 9.8 parts of urethane are dissolved in 300 parts of anhydrous Xylene in a suitable vessel equipped with an efficient distillation column. Xylene is distilled to remove traces of water from the mixture. 2.3 parts of aluminum isopropylate are added and distillation is continued until substantially the theoretical quantity of ethanol has been distilled at about 78 C. The reaction mixture is then freed from xylene by distillation under reduced pressure. Approximately 100 parts of water are added and the mixture again freed of solvent by distillation under reduced pressure. 100 parts of trichloroethylene are added, the solution filtered to remove insoluble matter and the solution freed of solvent by evaporation. The residual oil is purified by molecular distillation at a pressure of about 0.01 mm. 8.7 parts (35% of theoretical yield) of purified N-isobutyl-Z- methyl-Z-propyl-1,3-propanediol dicarbamate are obtained in the form of a viscous colorless'oil having the analytical values and physical constants listed in Table I.

anem a EXAMPLE 6 Preparation of N-allyI-Z-methyl-Z-prapyl-I,S-propanediol dicarbamate A solution of 18.1 parts of N-allyl-Z-methyl-Z-propyl- 3-hydroxypropyl carbamate, 8.9 parts of urethane and 200 parts of xylene are distilled to remove all traces of residual water. The mixture is allowed to cool and one part of aluminum isopropylate is added. The mixture is distilled until substantially the theoretical quantity of alcohol has been removed in the form of its azeotrope with xylene. The xylene is removed by distillation under reduced pressure and 100 parts of water are added. The water is distilled under reduced pressure and the residue dissolved in 150 parts of isopropanol. The insoluble material is removed by filtration and the isopropanol removed by distillation. The residual oil is purified by molecular distillation using a bath temperature of about l10135 and a pressure of about 0.025 mm. A yield of 14 parts of purified product is obtained having the analytical values and physical constants given in Table I. p

EXAMPLE 7 Preparation of N-propargyl-2-methyl-2-propyl-1,3-propanediol dicarbamate V N-propargyl-2-methyl-2-propyl-3-hydroxypropyl carbamate and urethane were reacted in an ester exchange reaction as described in Example 6. The product was purified by molecular distillation and the purified com- EXAMPLE 8 Preparation of N-propyl-Z-methyl-Z-propyl-l,3-propanedial dicarbamate A cooled 10% solution of 0.1 mole of phosgene in toluene was added with stirring to a cooled solution of 0.1 mole of 2-methyl-2-propyl-3-hydroxypropyl carbamate and 0.11 mole of pyridine also dissolved in toluene, at such a rate that the temperature of the mixture was maintained'at about to C. The mixture was allowed to warm 25 and was stirred for several hours. The pyridine hydrochloride was filtered 01f, the toluene was removed by distillation under reduced pressure and the residue dissolved in anhydrous ether. The solution was filtered and the chlorocarbonate used in the subsequent reactions in the form of its solution in anhydrous ether. To this solution there was added 0.2 mole of propylamine and the mixture was allowed to react at room tempera- .ture. The excess amine was removed by extracting with dilute hydrochloric acid solution, and the ether layer concentrated by evaporation of the solvent. The residue was purified by distillation under reduced pressure giving a product identical to that obtained in Example 1.

EXAMPLE 9 Preparation of N-allyl-2-methyl-Z-isopropyl-J,3-propanediol dicarbamate Z-methyl-Z-isopropyl-3-hydroxypropyl carbamate was .converted to its chlorocarbomate derivative employing EXAMPLE 10 Preparation of N-propargyl-Z-ethyl-2-n-butyl-1,3-propanediol dicarbamate EXAMPLE 11 Preparation of N-propyl-2-methyl-2-propyl-1,3-pr0panedial dicarbamate N-propyl-2-methyl-2-propyl-3-hydroxypropyl carbamate was converted to its chlorocarbonate derivative employing phospene and pyridine as described in Example 8. A solution of this chlorocarbonate in ether was treated at room temperature with an excess of dry ammonia gas by bubbling the gas into the stirred solution of the chlorocarbonate while cooling. The mixture was allowed to warm to room temperature and stirred for about one hour. The excess ammonia was removed by extracting with dilute hydrochloric acid and the isolation and purification effected as described in Example 8. The product obtained was identical to that obtained in Examples 1 and 8.

' EXAMPLE 12.

Preparation of N-n-butyl-2-methyl-Z-propyl-1,3-propanediol dicarbamate 175 parts of 2-methyl-2-propyl-3-hydroxypropyl carbamate and 108 parts of n-butyl isocyanate are added to 1250 parts of anhydrous benzol and the mixture boiled under reflux for about 8 hours. The solvent is removed by distillation under reduced pressure and the residue dissolved in approximately 1800 parts of warm trichloroethylene-hexane (1:2) solvent. On cooling, the product separates in the form of colorless crystals, which after removal from the solvent and drying, melts at 49 to 51 C. The yield of the purified compound is about of theoretical. Analysis: Calculated for nitrogen 10.21%; Found: nitrogen 10.42%. This compound may also be purified by distillation under reduced pressure. The compound distills at approximately 152 C. at a pressure of 0.06 mm. The product obtained by distillation can be converted to a crystalline solid by subjecting it to the crystallization procedure indicated above.

Other compounds prepared using this procedure were N-propyl-2-methyl-2-ethyl-1,3-propanediol dicarbamate, N-isopropyl-Z-methyl-Z ethyl 1,3 propanediol dicarbamate, N-n-butyl-Z-methyl-Z-ethyl-1,3-propanediol' dicarbamate and N-propyl-2-methyl-2-n-butyl-1,3-propanediol dicarbamate.

EXAMPLE 13 Preparation of N-isopropyl-Z-methyl-Z propyl 1,3 propanediol dicarbamate 21.7 grams (0.1 mole) of N-isopropyl-2-methyl-2-propyl-3-hydroxypropyl carbamate and 7.5 grams (0.11 mole) of anhydrous sodium cyanate are stirred in 200 mls. anhydrous chloroform in a suitable vessel equipped with a gas inlet tube, stirrer and thermometer. While cooling the vessel, anhydrous hydrogen chloride is passed into the stirred mixture slowly for 5 hours maintaining the 13 temperature between and 0 The mixture is then allowed to stand at room temperature overnight. The solid material is separated by filtration and the chloroform solution concentrated to' an oil under reduced pres- I sure. The oil is dissolved in 50 mls. of trichloroethylene,

the solution treated with charcoal, filtered and'thefiltrate added to 125 ml. of hexane. The crystalline-material which forms on standing at refrigerator temperature is removed by filtration, washed with light petroleum ether and dried at about 50 C. Approximately 20 grams of product are obtained. On recrystallizing from trichloroethylene-hexane, 17.8 grams of purified compound are obtained, melting point 8991 C. The product from EXAMPLE 14 Preparation of N-allyl-Z-methyl-Z-sec.-butyl-1,3-pr0panedial dicarbamate 0.1 mole of N-allyl-Z-methyl-Z-sec.-buty1-3-hydroxypropyl carbamate and 0.11 mole of anhydrous sodium cyanate are reacted in chloroform through the action of anhydrous hydrogen chloride as described in Example 13. The product was purified by molecular distillation and had the physical properties and analytical values. as given in Table 1.

EXAMPLE 15 Preparation of N-propargyl-2-methyl-2-sec.-butyl-1,3-pr0- panediol dicarbamate This compound was prepared from the corresponding N-propargyl monocarbamate and cyanic acid following the procedure described in Example 13. The product, purified by molecular distillation, had the analytical values and physical constants as given in Table 1.

EXAMPLE 16 Preparation of N-allyl-2,2-diethyl-1,3-pr0panedi0l dicarbamate To 17.5 grams of 2,2-diethyl-3-hydroxypropyl carbamate and 9.5 grams of pyridine in 150 m1. of dichloromethane there was added slowly with stirring 17.1 grams of phenylchlorocarbonate in 50 ml. of dichloromethane. After permitting the reaction to proceed for two hours at room temperature the solvent was removed under reduced pressure. The liquid residue was heated under reflux for six hours with 50 ml. of 50% aqueous allylamine. The resulting mixture was concentrated under reduced pressure, the residue dissolved in ether was extracted with dilute hydrochloric acid and then with aqueous potassium carbonate solution and dried over anhydrous potassium carbonate. The solvent was removed and the residue crystallized by addition of a hexane-ether mixture. 12 grams of purified product were obtained having the analytical values and physical constants given for this compound in Table 1.

Also prepared by this method were N-allyl-2-methyl-2- ethyl-1,3-propanediol dioarbamate and N-isopropyl-2- methyl-Z-n-butyl-1,3-propanediol dicarbamate. These compounds have the physical constants and analytical values as given in Table 1.

In addition to possessing unique muscle relaxant action so as to be extremely useful as a drug for the relief of muscle spasm, the marked central depressant properties and the hypotensive action of the compounds of this invention suggest that some of these compounds may be of further therapeutic value as tranquilizers, sedatives, hypnodes and agents influencing abnormal behavior and r lieving high blood pressure. I

The novel compounds of this invention are preferably administered orally in the form of pills, tablets, capsules or solutions formed by well known methods. When the active ingredient is in the form of a solid, atypical tablet composition comprises 0.5 gram of active ingredient, intermixed in a dry pulverulent state with gelatin, starch, magnesium stearate and alginic acid, pressed into a tablet. If the active ingredient is in the form of a liquid, it is dissolved in a suitable solvent. In general, an effective dose of the active ingredient is in the range of about 0.05 gram to about 2 grams.

This application is a continuation-in-part of application Ser. No. 729,235, filed April 18, 1958-, which. in turn is a continuation-in-part of application Ser. No. 654,664, filed April 24, 1957, both now abandoned.

What is claimed is:

1. The N-monosubstituted -2,2-dialkyl-1,3 propanediol dicarbamate selected from the group consisting of N-propargyl-2-methyl-2-n-butyl 1,3 propanediol dicarbamate, N-propyl-2-methyl-2-sec.butyl-1,3 propanediol dicarbamate, N-isopropyl-2-methyl-2-sec.butyl 1,3 propanediol dicarbamate, N-allyl-2-methyl-2-sec.butyl-1,3-propanediol dicarbamate, N-propargyl-2-methyl-2-sec.butyl-1,3 propanediol dicarbamate, N-propyl-Z-ethyl-2-ethyl-1,3-propanediol dicarbamate, N-isopropyl-Z-ethyl-Z-ethyl-1,3-propanediol dicarbamate, N-allyl-2-ethyl-2-ethyl-1,3-propanediol dicarbamate, N-isopropyl-2-ethyl-2-n-propyl-1,3-propanediol dicarbamate,

N-isopropyl-2-ethyl-2-isopropyl 1,3 propanediol dicarbamate,

N-methyl-2-ethyl-2-n-butyl-1,3 propanediol dicarbamate,

and

N-propargyl-2-ethyl-2-n-butyl-1,3 propanediol dicarbamate.

2. N-isopropyl-2-methyl-2-propyl 1,3 propanediol dicarbamate.

3. N-n-butyl-2-methyl-2-propyl-1,3 -propanediol dicarbamate.

4. N-allyl-2-methyl-2-propyl-1,3-propanedi0l dicarbamate.

15 5. N-propargyLZ-methyl-Z-propyl-1,3 propanediol dicarbamate. 1 V

6. N-propargyl-Z-methyl-Z-n-butyl-1,3 -pr0panediol dicarbamate.

7. The method of relaxing muscles of an animal comprising administering internally to the animal a compound selected fromthe group consisting of ate,

N-allyl-2-methyl-2-propyl-1,3-propanediol dicarbamate,

N-propargyl-Z-methyl-2-propyl-1,3-propanediol dicarbamate,

N-isopropyl-2-methyl-2-isopr0pyl-1,3 propanediol dicarbamate,

N-n-butyl-Z-methyl-2-isopropyl 1,3 propanediol dican bamate,

N-ally1-2-methyl-Z-isopropyl-1,3-propanediol dicarbamate,

N-methyl-2-methyl-2-n-butyl-1,3 propanediol dicarbamate, N-propyl-Z-methyl-Z-n-butyl-1,3 propanediol dicarbamate, 7 N-isopropyl-2-methy1-2-n-butyl-1,3-propanedio1 dicarbamate,

- l6 N-a1lyl-2-methy1-2-n-butyl-1,3-propanedio1 dicarbamate, N-propargyl-Z-methyl-Z-n-butyl 1,3 propanediol dicarbamate, Y I

N-propyl-2-methyl-2-sec.butyl-1,3 propanediol dicarbamate,

N-isopropyl-2-methyl-2-sec.butyl 1,3 propanediol dicarbamate, V

N-ally1-2-methyl-2-sec.butyl-1,3-propanediol dicarbamate,

N-propargyl-2-methyl-2-sec.butyl-1,3 propanediol dicarbamate,

N-propyl-2-ethyl-2-ethyl-1,3-propanediol dicarbamate,

N-isopropyl-Z-ethyl-2-ethy1-1,3-propanediol dicarbamate,

N-allyl-Z-ethyl-Z-ethyl-1,3-propanediol dicarbamate,

N-isopropyl-2-ethyl-2-n-propyl-1,3-propanediol dicarbamate,

N-isopropyl-2-ethyl-2-isopropyl 1,3 propanediol dicarbamate,

N-methyl-Z-ethyl-2-n-butyl-1,3 propanediol dicarbamate,

and

N-propargyl-Z-ethy1-2-n-buty1-1,3 propanediol dicarbamate,

said compound being in an amount which is non-toxic and sufficient to exert muscle relaxant activity.

References Cited in the file of this patent OTHER REFERENCES 2,197,479 Meigs Apr. 16, 1940 2,697,720 Kaiser Dec. 21, 1954 2,724,720 Berger Nov. 22, 1955 OTHER REFERENCES Sidgwicks Organic Chemistry of Nitrogen (1949), page 332.

UNITED STATES PATENT OFFICE CERTIFICATION OF CORRECTION Patent No. 2,937,119

May 17 1960 Frank M. Berger et al.

It is hereby certified that error appears in the above numbered patent requiring correction and that the said Letters Patent should read as corrected below.

Column 3, under the heading TABLE III, the formula should appear as shown below instead'as in the patent:

Signed and sealed this 24th day of October 1961a (sEAL) 'Attest:

ERNEST W. SWIDER DAVID L, LADD Attesting Officer Commissioner of Patents 

1. THE N-MONOSUBSTITUTED-2,2-DIALKYL-1,3 - PROPANEDIOL DICARBAMATE SELECTED FROM THE GROUP CONSISTING OF N-PROPYL-2-METHYL-2-ETHYL-1,3-PROPANEDIOL DICARBAMATE, N-ISOPROPYL-2-METHYL-2-ETHYL-1,3 - PROPANEDIOL DICARBAMATE, N-N-BUTYL-2-METHYL-2-ETHYL-1,3-PROPANEDIOL DICARBAMATE, N-ALLYL-2-METHYL-2-ETHYL-1,3-PROPANEDIOL DICARBAMATE, N-ETHYL-2-METHYL-2-PROPYL-1,3-PROPANEDIOL DICARBAMATE, N-PROPYL-2-METHYL-2-PROPYL-1,3-PROPANEDIOL DICARBAMATE, N-ISOPROPYL-2-METHYL-2-PROPYL-1,3-PROPANEDIOL DICARBAMATE, N-N-BUTYL-2-METHYL-2-PROPYL-1,3-PROPANEDIOL DICARBAMATE, N-ISOBUTYL-2-METHYL-2-PROPYL-1,3 - PROPANEDIOL DICARBAMATE, N-ALLYL-2-METHYL-2-PROPYL-1,3-PROPANEDIOL DICARBAMATE, N-PROPARGYL-2-METHYL-2-PROPYL-1,3-PROPANEDIOL DICARBAMATE, N-ISOPROPYL-2-METHYL-2-ISOPROPYL-1,3 - PROPANEDIOL DICARBAMATE, ATE N-N-BUTYL-2-METHYL-2-ISOPROPYL - 1,3 - PROPANEDIOL DICARBAMATE, N-ALLYL-2-METHYL-2-ISOPROPYL-1,3 - PROPANEDIOL DICARBAMATE, N-METHYL-2-METHYL-2-N-BUTYL-1,3 - PROPANEDIOL DICARBAMATE, N-PROPYL-2-METHYL-2-N-BUTYL-1,3-PROPANEDIOL DICARBAMATE, N-ISOPROPYL-2-METHYL-2-N-BUTYL-1,3-PROPANEDIOL DICARBAMATE, N-ALLYL-2-METHYL-2-N-BUTYL-1,3-PROPANEDIOL DICARBAMATE, N-PROPARGYL-2-METHYL-2-N-BUTYL-1,3 - PROPANEDIOL DICARBAMATE, N-PROPYL-2-METHYL-2-SEC.BUTYL-1,3-PROPANEDIOL DICARBAMATE, N-ISOPROPYL-2-METHYL-2-SEC.BUTYL -1,3 - PROPANEDIOL DICARBAMATE, N-ALLYL-2-METHYL-2-SEC. BUTYL-1,3-PROPANEDIOL DICARBAMATE, N-PROPARGYL-2-METHYL-2-SEC.BUTYL-1,3 - PROPANEDIOL DICARBAMATE, N-PROPYL-2-ETHYL-2-ETHYL-1,3-PROPANEDIOL DICARBAMATE, N-ISOPROPYL-2-ETHYL-2-ETHYL-1,3-PROPANEDIOL DICARBAMATE, N-ALLYL-2-ETHYL-2-ETHYL-1,3-PROPANEDIOL DICARBAMATE, N-ISOPROPYL-2-ETHYL-2-N-PROPYL-1,3-PROPANEDIOL DICARBAMATE, N-ISOPROPYL-2-ETHYL-2-ISOPROPYL -1,3 - PROPANEDIOL DICARBAMATE, N-METHYL-2-ETHYL-2-N-BUTYL-1,3 - PROPANEDIOL DICARBAMATE, AND N-PROPARGYL-2-ETHYL-2-N-BUTYL-1,3 - PROPANEDIOL DICARBAM
 7. THE METHOD OF RELAXING MUSCLES OF AN ANIMAL COMPRISING ADMINISTERING INTERNALLY TO THE ANIMAL A COMPOUND SELECTED FROM THE GROUP CONSISTING OF N-PROPYL-2-METHYL-2-ETHYL-1,3-PROPANEDIOL DICARBAMATE, N-ISOPROPYL-2-METHYL-2-ETHYL-1,3 - PROPANEDIOL DICARBAMATE, N-N-BUTYL-2-METHYL-2-ETHYL-1,3-PROPANEDIOL DICARBAMATE, N-ALLYL-2-METHYL-2-ETHYL-1,3-PROPANEDIOL DICARBAMATE, N-ETHYL-2-METHYL-2-PROPYL-1,3-PROPANEDIOL DICARBAMATE, N-PROPYL-2-METHYL-2-PROPYL-1,3-PROPANEDIOL DICARBAMATE, N-ISOPROPYL-2-METHYL-2-PROPYL-1,3-PROPANEDIOL DICARBAMATE, N-N-BUTYL-2-METHYL-2-PROPYL-1,3-PROPANEDIOL DICARBAMATE, N-ISOBUTYL-2-METHYL-2-PROPYL-1,3 - PROPANEDIOL DICARBAMATE, N-ALLYL-2-METHYL-2-PROPYL-1,3-PROPANEDIOL DICARBAMATE, N-PROPARGYL-2-METHYL-2-PROPYL-1,3-PROPANEDIOL DICARBAMATE, N-ISOPROPYL-2-METHYL-2-ISOPROPYL-1,3 - PROPANEDIOL DICARBAMATE, N-N-BUTYL-2-METHYL-2-ISOPROPYL - 1,3 - PROPANEDIOL DICARBAMATE, N-ALLYL-2-METHYL-2-ISOPROPYL-1,3-PROPANEDIOL DICARBAMATE, N-METHYL-2-METHYL-2-N-BUTYL-1,3 - PROPANEDIOL DICARBAMATE, N-PROPYL-2-METHYL-2-N-BUTYL-1,3 - PROPANEDIOL DICARBAMATE, N-ISOPROPYL-2-METHYL-2-N-BUTYL-1,3-PROPANEDIOL DICARBAMATE, N-ALLYL-2-METHYL-2-N-BUTYL-1,3-PROPANEDIOL DICARBAMATE, N-PROPARGYL-2-METHYL-2-N-BUTYL - 1,3 - PROPANEDIOL DICARBAMATE, N-PROPYL-2-METHYL-2-SEC.BUTYL-1,3 - PROPANEDIOL DICARBAMATE, N-ISOPROPYL-2-METHYL-2-SEC.BUTYL - 1,3 - PROPANEDIOL DICARBAMATE, N-ALLYL-2-METHYL-2-SEC.BUTYL-1,3-PROPANEDIOL DICARBAMATE, N-PROPARGYL-2-METHYL-2-SEC.BUTYL-1,3 - PROPANEDIOL DICARBAMATE, N-PROPYL-2-ETHYL-2-ETHYL-1,3-PROPANEDIOL DICARBAMATE, N-ISOPROPYL-2-ETHYL-2-ETHYL-1,3-PROPANEDIOL DICARBAMATE, N-ALLYL-2-ETHYL-2-ETHYL-1,3-PROPANEDIOL DICARBAMATE, N-ISOPROPYL-2-ETHYL-2-N-PROPYL-1,3-PROPANEDIOL DICARBAMATE, N-ISOPROPYL-2-ETHYL-2--ISOPROPYL - 1,3 - PROPANEDIOL DICARBAMATE, N-METHYL-2-ETHYL-2-N-BUTYL-1,3 - PROPANEDIOL DICARBAMATE, AND N-PROPARGYL-2-ETHYL-2-N-BUTYL-1,3 - PROPANEDIOL DICARBAMATE, SAID COMPOUND BEING IN AN AMOUNT WHICH IS NON-TOXIC AND SUFFICIENT TO EXERT MUSCLE RELAXANT ACTIVITY. 